Abiraterone Acetate (Page 3 of 7)

6.2 Post Marketing Experience

The following additional adverse reactions have been identified during post approval use of abiraterone acetate with prednisone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Respiratory, Thoracic and Mediastinal Disorders: non-infectious pneumonitis.
Musculoskeletal and Connective Tissue Disorders: myopathy, including rhabdomyolysis.
Hepatobiliary Disorders: fulminant hepatitis, including acute hepatic failure and death.

7 DRUG INTERACTIONS

7.1 Drugs that Inhibit or Induce CYP3A4 Enzymes

Based on in vitro data, abiraterone acetate is a substrate of CYP3A4.
In a dedicated drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during abiraterone acetate treatment. If a strong CYP3A4 inducer must be co-administered, increase the abiraterone acetate dosing frequency [see Dosage and Administration (2.5)and Clinical Pharmacology (12.3)].
In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone [see Clinical Pharmacology (12.3) ].

7.2 Effects of Abiraterone on Drug Metabolizing Enzymes

Abiraterone acetate is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6 and CYP2C8. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3)].

In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone (CYP2C8 substrate) was increased by 46% when pioglitazone was given together with a single dose of 1,000 mg abiraterone acetate. Therefore, patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with abiraterone acetate [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

8.2 Lactation

Risk Summary
Abiraterone acetate is not indicated for use in women. There is no information available on the presence of abiraterone acetate in human milk, or on the effects on the breastfed child or milk production.

8.1 Pregnancy

Risk Summary
Based on findings from animal studies and the mechanism of action, abiraterone acetate is contraindicated for use in pregnant women because the drug can cause fetal harm and potential loss of pregnancy. Abiraterone acetateis not indicated for use in females.
There are no human data on the use of abiraterone acetate in pregnant women. In animal reproduction studies, oral administration of abiraterone acetate to pregnant rats during organogenesis caused adverse developmental effects at maternal exposures approximately ≥ 0.03 times the human exposure (AUC) at the recommended dose (see Data).
Data
Animal Data
In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused material toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients.

8.3 Females and Males of Reproductive Potential

Contraception
Males
Based on findings in animal reproduction studies and its mechanism of action, advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 weeks after the final dose of abiraterone acetate [see Use in Specific Populations (8.1)].

Infertility
Based on animal studies, abiraterone acetate may impair reproductive function and fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

Safety and effectiveness of abiraterone acetate in pediatric patients have not been established.

8.5 Geriatric Use

Of the total number of patients receiving abiraterone acetate in randomized clinical trials, 70%of patients were 65 years and over and 27% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Patients with Hepatic Impairment

The pharmacokinetics of abiraterone were examined in subjects with baseline mild (N=8) or moderate (N=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of abiraterone acetate increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function.
In another trial, the pharmacokinetics of abiraterone were examined in subjects with baseline severe (N=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone increased by approximately 7-fold and the fraction of free drug increased 2-fold in subjects with severe baseline hepatic impairment compared to subjects with normal hepatic function.
No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of abiraterone acetate to 250 mg once daily. Do not use abiraterone acetate in patients with baseline severe hepatic impairment (Child-Pugh Class C). If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue abiraterone acetate treatment [see Dosage and Administration (2.4)and Clinical Pharmacology (12.3)].
For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.4),

Warnings and Precautions (5.3) , and Clinical Pharmacology (12.3) ].

8.7 Patients with Renal Impairment

No dosage adjustment is necessary for patients with renal impairment [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE

Human experience of overdose with abiraterone acetate is limited. There is no specific antidote. In the event of an overdose, stop abiraterone acetate, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function.

11 DESCRIPTION

Abiraterone acetate, the active ingredient of abiraterone acetate tablets, USP is the acetyl ester of abiraterone. Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each abiraterone acetate tablet contains either 250 mg of abiraterone acetate. Abiraterone acetate is designated chemically as (3β)-17-(3-pyridinyl) androsta-5,16-dien-3-yl acetate and its structure is:

structure
(click image for full-size original)

Abiraterone Acetate USP is a white to off-white, non-hygroscopic, crystalline powder. Its molecular formula is C26 H33 NO2 and it has a molecular weight of 391.55. Abiraterone acetate is a lipophilic compound with an octanol-water partition coefficient of 3.57 and is practically insoluble in water. The pKa at about 25°C is 3.06.
Abiraterone acetate tablets, USP are available in 250 mg uncoated tablets with the following inactive ingredients:

colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and sodium lauryl sulfate.

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